PROJECT SUMMARY/ABSTRACT Obsessive Compulsive Disorder (OCD) is a debilitating psychiatric illness with a complex etiology. Studies in humans have identified hyperactivity of corticostriatal circuits in patients with OCD. Furthermore, twin and family studies show a significant role for genetics in the etiology of OCD, with multiple studies identifying association of polymorphisms in the gene SLC1A1 with OCD. The most common of these OCD- associated polymorphisms increases expression of the encoded protein ? the neuronal glutamate transporter, excitatory amino acid transporter-3 (EAAT3). This OCD-linked allele is associated with increased SLC1A1 expression in lymphoblastoid cells, human postmortem brain, a luciferase reporter assay, and transfected HEK cells, where there is also a functional increase in EAAT3 protein activity, as evidenced by increased glutamate uptake. There is also increased EAAT3 protein expression in striatum of Sapap3-knockout (KO) mice, a model of OCD-like behavior. These results suggest that increased SLC1A1 expression may result in increased generation of abnormal repetitive behaviors, and lead to the prediction that reducing EAAT3 may reduce compulsive behavior. Indeed, Slc1a1-STOP knock-in mice that have ablated EAAT3 protein expression and function show blunted responses during pharmacologically-induced repetitive behavior. Specifically, these mice have attenuated increases in stereotypy and hyperlocomotion in response to amphetamine, and attenuated grooming increases in response to a dopamine D1 receptor agonist. In addition, preliminary data indicate that a specific EAAT3 inhibitor (EAAT3i) can reduce compulsive-like behavior. Chronic EAAT3i administration reduced amphetamine-induced hyperlocomotion, and acute administration decreased grooming in a mouse model of autism-like behavior. However, the role of EAAT3 in OCD-like behavior and associated corticostriatal circuit activity has not been studied. I will therefore use advanced neuroscience tools to determine if chronic ablation and/or acute inhibition of EAAT3 normalizes behavior and striatal activity in a mouse model of OCD-like behavior, and directly test whether EAAT3 overexpression causes OCD-like behavior. My overarching hypothesis is that EAAT3 is necessary and sufficient for the development and expression of OCD-like behavior in mice.